Umbrella analysis of the effect of renin-angiotensin-aldosterone system inhibitors on COVID-19 related outcomes

In a recent study posted to the medRxiv* preprint server, researchers conducted an umbrella review and meta-analysis of the renin-angiotensin-aldosterone system (RAAS) inhibitors' impact on coronavirus disease 2019 (COVID-19) clinical outcomes.

Study: An umbrella review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 outcomes: what do we know so far?. Image Credit: ker_vii/Shutterstock
Study: An umbrella review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 outcomes: what do we know so far?. Image Credit: ker_vii/Shutterstock

Background

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with symptoms like persistent cough and fever. In extreme cases, SARS-CoV-2-infected individuals need hospitalization and ventilatory support. Risk factors associated with poor clinical outcomes in COVID-19 include gender, age, and cardiovascular disease conditions such as hypertension. 

The influence of RAAS inhibitors on SARS-CoV-2 outcomes has garnered a lot of attention owing to their ubiquitous use across people at risk of poor clinical outcomes. Another factor that aroused interest in the effects of RAAS inhibitors in COVID-19 outcomes was their modes of action, specifically, the potential increased expression of angiotensin-converting enzyme 2 (ACE2), which is linked to SARS-CoV-2 entrance into bronchial cells. Nevertheless, the impact of RAAS inhibitors like angiotensin-receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) on SARS-CoV-2 outcomes is still contentious based on the proof from numerous meta-analyses.

About the study

In the current umbrella review and meta-analysis, the researchers conducted a comprehensive analysis of existing systematic reviews and meta-analyses on the impact of ARBs/ACEIs on SARS-CoV-2-associated outcomes. Data was gathered from medRxiv, the Cochrane Library, Scopus, Embase, and Medline (OVID) databases using keywords such as COVID-19, renin-angiotensin system, angiotensin II receptor antagonists, and angiotensin-converting enzyme inhibitors from the inception of the study until February 1, 2021. Studies in the English language published from 2019 were included in the current review. 

Systematic reviews containing meta-analyses of impacts of ACEIs/ARBs on SARS-CoV-2-linked clinical outcomes were considered eligible for the current umbrella review. Adults aged 18 years or older in real-world settings with and without a SARS-CoV-2 diagnosis were eligible for the research. The exposure of interest was RAAS inhibitor (ARBs and ACEIs) therapy compared with those with no exposure to RAAS inhibitors. Reviews that compared patients treated with ACEIs versus ARBs were also included.

The present study's outcomes of interest were SARS-CoV-2 infection risk and COVID-19-associated clinical outcome, including yet not restricted to mortality; severity of SARS-CoV-2 infection; intensive care unit (ICU) admission; hospitalization; hospital discharge; duration of hospital stay; readmission to hospital; pneumonia severity; acute respiratory distress syndrome; cardiac injury; and septic shock.

A total of 47 eligible systematic reviews reporting 213 meta-analyses were included in the present study. Two reviewers independently retrieved data and evaluated the studies' risk of bias employing the AMSTAR 2 Critical Appraisal Tool. Pooled results were integrated using the random-effects meta-analysis approach, including numerous subgroup studies.

Findings

The results indicated that although the amount of the observed influence of ACEIs/ARBs on death reduction decreased as study quality increased, the evidence was generally comparable across all subgroup evaluations. The evidence quality was even better in death/ICU admission since the impact of ACEI/ARB therapy was robust only among moderate-quality publications, peer-reviewed studies, and investigations with hypertensive patients. The effect was relevant irrespective of whether the measure of impacts was adjusted or crude, albeit it was higher among publications with the adjusted measure of effects relative to a 13% drop among studies using the crude measure of effects.

On the contrary, the evidence supporting the influence of ARBs/ACEIs on severe SARS-CoV-2 was of low quality, as a relevant decrease was only seen in trials with very low quality. As the quality of the study improved from severely low to low or moderate, the substantial connection vanished.

The quality of the evidence on the influence of ARBs/ACEIs on hospitalization was poor since a significant connection was not evident when the data were evaluated by study quality, even though the magnitude of the impact was nearly constant across studies of varying quality. Furthermore, only studies that provided adjusted measures of effects, non-peer-reviewed studies, and analyses that did not acknowledge the hypertensive state of their study group showed a substantial increase in hospitalization.

In addition, the subgroup analyses revealed some low-quality data for the influence of ARBs and ACEIs as distinct entities. While ARB therapy correlated with a dramatic rise in hospitalization only in low-quality and non-peer-reviewed investigations, ACEI therapy was associated with a significant increase in hospitalization by 23% only in studies that did not indicate the hypertensive condition of the study group.

The limitations of the current review include the chances of unquantified confounding. Further, of the 47 included studies, only ten were of average quality.

Conclusions

According to the authors, this is the first umbrella review combining all existing observational reports on the influence of ARBs and ACEIs on SARS-CoV-2 clinical outcomes into a single pooled estimate. The study findings demonstrated a strong link between the ARBs/ACEIs use and a lower risk of mortality and death/ICU admission. However, there was limited proof for the use of these drugs and less incidence of severe SARS-CoV-2 infection and increasing infection-related hospitalization. Therefore, cautious interpretation of these results is advised.

Altogether, the present study corroborates the existing recommendation for COVID-19 patients to continue ARBs/ACEIs therapy. This was due to the absence of good quality information on their harmful effects. Besides, the current findings indicate that ARBs and ACEIs therapy may be advantageous to COVID-19 patients.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Shanet Susan Alex

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.

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